WEEK 8 - drug redeployment and cancer Flashcards
problem with new drug discovery
it is slow and expensive
average 15 years and 800 million US$ to reach market
one solution to expensive and new drug discovery
identify new uses of existing drugs
Many drugs coming to market now are improved version of drugs we already had
drug redeployment:
positives
can save time and expense
drug redeployment:
existing drugs have known..
pharmacokinetics and safety profiles
drug redeployment:
most often approved by..
regulatory agencies for human use
drug redeployment:
rapid evaluation
newly-identified uses can be rapidly evaluated in phase II clinical trials
drug redeployment:
what assessments can be eliminated
drug developers can eliminate much of the toxicological and pharmacokinetics assessments
drug redeployment:
acute promyelocytic leukaemia
all trans retinoic ATRA
approved by the shanghai municipality for the treatment of skin diseases such as psoriasis and acne
demonstrated that ATRA strongly induces terminal differentiation of HL-60 and fresh APL cells
1985 the first APL patient treated with ATRA in shanghia
- Retinoic acid alongside chemo
ATRA induces terminal differentiation of abnormal promyelocytes in vivo
drug redeployment:
acute promyelocytic leukaemia
outcome
trials demonstrated that ATRA gave superior results to chemotherapy (The derivative of vitamin A outperforming chemotherapy)
ATRA/chemo in combination is superior to chemo or ATRA alone
the best outcome was observed in patients who received ATRA during both induction and maintenance chemotherapy with a 5-year disease free survival (DFS) of 74%
drug redeployment:
acute promyelocytic leukaemia:
molecular basis
the molecular basis of APL was discovered after the benefits of ATRA had been discovered
In this disease get a chromosomal rearrangement
Chromosome 17 and 15 recombine in some way and create a fusion gene
history of arsenic as a drug
a well known poison
one of the oldest drugs in both western medicine and traditional Chinese medicine
Hippocrates: treatment of skin ulcers
Chinese Treaty NeiJlng: treatment of malaria-associated periodic fever
18+19th C: for periodic fever, CML and other diseases
arsenic
why was it stopped being used
was discarded as a treatment in the early 20thC because of its toxicity and the advent of radiatiion and cytotoxic CT
- Toxicity considered to be too unpredictable
So radiotherapy regimes were preferred over the use of arsenic
arsenic-reborn
in early 1970s
group from Harbin medical uni in NE china
identified arsenic trioxide (ATO) as an active ingredient from an ancient anticancer remedy
used an arsenic compound to treat a variety of cancers
arsenic-reborn
cancer treatment
in 1992
a crude solution of Arsenic trioxide (ATO) composed of 1% ATP with a trace amount of mercury chloride induced complete remisiion in 21 of 32 acute promyelocytic leukaemia patients
confirmed by further independent studies in the late 1990s
recent studies have identified that ATO as a single agent produces respectable rates of long-term remission in newly diagnosed patients
ARTRA/ATO combination as a synergistic therapy
studies in a PML/RAR mouse model and in human NB4 APL cell line
mouse model indicated that ATRA/ATO combination could dramatically prolong the survival or even eradicate disease in animals
these results have encouraged clinical trials using ATRA/ATO combination to treat newly diagnosed APL
- without any conventional chemo
Kaplan-Meier survival curves
shows overall survival over 5 years
ARTRA/ATO combination as a synergistic therapy:
positives of treatment
With this treatment don’t get anywhere need the toxicities that you do with traditional chemotherapy
Part of the reason that survival is better
- Because you get less treatment related deaths
clinical trials
representation of normal public?
THAT CLINICAL TRIALS DO NOT REPRESENT THE NORMAL PUBLIC!!
- Clinical trials always have exclusion criteria
- In cancer trials this is usually the exclusion of older patients
○ Frailer and less likely to tolerate the treatment
In real world more like 70-65% survival
ATRA treatment leads to elimination of…
PML-RARa-positive cells
ATRA treatment
why is it successful
Much lower residual disease with this combination than with either alone
This combination of drug is successful because if effects many pathways in leukaemia cells
- So very difficult to find a leukaemia cell that will mutate its way out of the problem
- So resistant to this treatment is much lower (than any other treatment)
thalidomide in Myeloma:
history
thalidomide thought to have been developed by pharmaceutical company Grunnethal in germany
sold from 1957 to 1961 in almost 100 countries under at least 40 names
prescribes ot pregnant women to combat nausea and aid sleep
inadequate tests to asses drugs safety
- catastrophic results for children of women who had taken drug during pregnancies
approx. 10,000 children in Africa and Europe were born with severe malformities including phocomelia (short or absent long bones)
the thalidomide tragedy
approx. 10,000 children in Africa and Europe were born with severe malformities including phocomelia (short or absent long bones)
the thalidomide tragedy
in USA
impact was minimized
Frances Oldham Kelsey refused FDA-approval from an application to market thalidomide saying it needed more study
the applicant gave the tablets to doctors with the understanding that it was still under investigation
17 children in the US were born with the defects
Thalidomide and leprosy
1964 israeli physician Jacon Sheskin sought to help a critically ill patient with erythema nodosum leprosum (ENL) a painful complication of leprosy
found a bottle of thalidomide tablets and remembered that it had been effective in helping mentally ill patients sleep
administered two tablets thalidomide:
- the patient slept for hours
- was able to get out of bed without aid upon awakening
- has resulted in the closure of many leprosy hospitals
